L-3-hydroxy-6-oxo-n-cyclopropylmethylmorphinans

ABSTRACT

A L-3-HYDROXY-6-OXOMORPHINAN COMPOUND REPRESENTED BY THE FORMULA:   10A-R,11-R2,6-HO,3-(O=)-1,2,3,9,10,10A-HEXAHYDRO-4H-10,   4A-IMINOETHANOPHENANTHRENE WHERE F IS C1,C2   WHEREIN R REPRESENTS A HYDROGEN ATOM OR A HYDROXYL GROUP, R1 REPRESENTS A CYCLOPROPYLMETHYL GROUP AND F REPRESENTS THE PRESENCE OR ABSENCE OF A DOUBLE BOND, BEING USEFUL AS A NARCOTIC ANTAGONIST, IS PREPARED BY INTRODUCING THE SUBSTITUENT AT THE N-POSITION.

nited States Patent 01 hce Patented June 12, 1973 U.S. Cl. 260-285 3 Claims ABSTRACT OF THE DISCLOSURE A L-3-hydroxy-6-oxomorphinan compound represented by the formula:

wherein R represents a hydrogen atom or a hydroxyl group, R represents a cyclopropylmethyl group and F represents the presence or absence of a double bond, being useful as a narcotic antagonist, is prepared by introducing the substituent at the N-position.

This application is a divisional application of application Ser. No. 807,917, filed Mar. 17, 1969, now U.S. Pat. No. 3,654,280.

The present invention relates to L-3-hydroxy-6-oxomorphinan compounds and their production. More particularly, it relates to L-3-hydroxy-6-oxomorphinan compounds useful as narcotic antagonists and their production.

The said L-3-hydroxy-6-oxomorphinan compound (L means herein a morphinan conformation similar to those derived from thebaine) is represented by the formula:

wherein R represents a hydrogen atom or a hydroxyl group, R represents a cyclopropylmethyl group and F represents the presence or absence of a double bond.

There have heretofore been known some narcotic antagonists. For instance, levallorphan tartrate (i.e. L-3-hydroxy-N-allylmorphinan tartrate) is commercially available as a narcotic antagonist. For the purpose of developing new narcotic antagonists, the present inventors have prepared many rnorphinan compounds, examined their narcotic antagonisms and discovered that, of these compounds examined, the said morphinan compounds ('I) have excellent narcotic antagonism is comparison with known narcotic antagonists. Thus, the present invention has been established.

Accordingly, a basic object of the present invention is to embody the L-3-hydroxy-6-oxornorphinan compound (I). Another object of this invention is to embody the L-3-hydroxy-6-oxomorphinan compound (I) useful as a narcotic antagonist. A further object of the invention is to embody a process for preparing the L-3-hydroxy-6- oxomorphinan compound (I). These and other objects will be apparent to those conversant with the art to which the present invention pertains from the subsequent description.

The said L-3-hydroxy-6-oxomorphinan compound (I) can be prepared by reacting a morphinan compound represented by the formula:

N-H J l O Law (II) wherein R represents a hydrogen atom or a hydroxyl group and F represents the presence or absence of a double bond with a halogen compound represented by the formula:

R -X (III) wherein R represents a cyclopropylmethyl group and X represents a halogen atom in an inert solvent medium.

The starting morphinan compound (II) illustratively involves L-3-hydroxy-6-oxomorphinan, L-3-hydroxy-6- oxo 7 dehydromorphinan, L-3,14-dihydroxy-6-oxomorphinan and L-3,14-dihydroxy-6-oxo-7-dehydromorphinan. These starting compounds can be prepared, for instance, by reacting an N-methylmorphinan with cyanogen bromide in chloroform to give an N-cyanomorphinan and treating the said product with hydrochloric acid while heating (Sawa et al.: U.S. Pat. 3,201,403). The said starting compound may be substituted with the corresponding 3-alkoxymorphinan compound as far as the latter is subjected to a conventional ether fission before the start of the present reaction. The halogen compound (HI) involves illustratively cyclopropylmethyl halide (e.g. cyclopropylmethyl chloride, cyclopropylmethylbromide, cyclopropylmethyl iodide).

The preparation of the L-3-hydroxy-6-oxomorphinan compound (I) is carried out by reacting the starting compound (II) with the halogen compound (III) in the presence of an inert solvent. The reaction temperature may be adopted suitably within the scope of a temperature from ice cooling temperature to refluxing temperature of the solvent used. Examples of the solvent are alcohols (e.g. methanol, ethanol, isopropanol), aromatic hydrocarbons (e.g. benzene, toluene, xylene), ethers (e. g. ether, dioxane, tetrahydrofuran, diglyme), dimethylforrrramide, di-methylsulfoxide and their mixture. The reaction may be effected more favorably in the presence of a conventional basic substance under nitrogen stream. As the basic substance, there are exemplified organic bases (e. g. pyridine, pycoline, dimethylaniline, triethylamine) and inorganic bases (e.g. sodium bicarbonate, potassium bicarbonate, sodium carbonate, potassium carbonate, sodium hydroxide, potassium hydroxide, lithium hydroxide, ammonium hydroxide, barium hydroxide). The solvent may be substituted for an excessive amount of the organic base. The objective substance of this invention may be isolated and purified in a conventional manner such as extraction, distillation, recrystallizatlOIi; column chromatography or thin layer chromatograp y.

TABLE Narcotic 1 antag- Acute onism toxicity 1! (EDso (LDaD, Compound mgJkg.) mg.lkg.)

Levallorphan tartrate 0. 23 200 L-3,14dihydroxy-6-oxo-N-cyclopropylmethyl- 0. 045 800 morphinan H2O 1 Narcotic antagonism was examined as follows: As test animals, there were used dds-strain albino male mice weighing 17 to 21 grams. This test was effected substantially according to a modified method of the Hafiner- Hesses method [Hessez Arch. exp. Path. u. Pharm., vol. 158, p. 233 (1930)]. Test animals were first treated with mg./kg. of morphine (showing 100% of the efiective dose) substantially and 6 minutes later test compounds intraperitoneally. Thirty minutes after the administration of the morphine, the tail of test mice was pinched by a forceps for pressure impetus. The narcotic antagonism was measured by confirming any response of the screams and bitings as an efiective indication. These percent effects were plotted against logarithmic dose on probability graphic paper and the effective dose (ED50) was determined by the method of Litchfiield and Wilcoxon.

2 Acute toxicity was examined as follows: Test compounds were applied subcutaneously to dds-strain albino mice in different single doses. For each dose 10 mice were used, their weight ranging from 17 to 21 grams. The animals were observed for 72 hours after the administration of the test compound. The LD.- was calculated by graphic interpolation for two doses actually used, one of which killed less than half and the other more than half the number of mice treated (Schleicher and Schull probability graphie paper 208% was used for the graphic interpolation).

Other L-3-hydroxy-6-oxomorphinan compounds (I) show similar narcotic antagonisms. Accordingly, the 'L-3-hydroxy-6-oxomorphinan compounds (I) and their acid addition salts are useful as narcotic antagonists. In addition to these narcotic antagonisms, they are also useful as less or non-narcotic analgesic, sedative and antitussive agents.

The said L-3-hydroxy-6-oxomorphinan compounds (I) may be administered alone or in combination with medically acceptable carriers, the choice of which is determined by the preferred route of administration, the solubility of the substance and standard pharmaceutical practice. In general, the dosage of these substances is of approximately one tenth to equal order of magnitude as the dosage of levallorphan tartrate, and the compounds of this invention is useful to treat patients suffering from painful conditions and side reactions ascribing to narcotic analgesic agents such as morphine. Examples of their pharmaceutical -prep arations are tablets, capsules, pills, suspension, solution, emulsion and suppositories. In the preparation of tablets, for example, these substances may be combined with binders such as gum tragacanth, acacia, cornstarch, gelatin, etc. It is also usually desirable to add a disintegrating agent such as cornstarch, potato starch, alginic acid or the like. Also usually desirable is a lubricant such as stearic acid, magnesium stearate or talc along with a sweetening agent such as saccharin. In the preparation of capsules, fillers as enumerated above for tablets can also be used. The composition when used in the form of suspension or solution may be combined with aqueous sugar or sorbitol type vehicle including a viscosity control agent such as magnesium aluminum silicate, methocel or carboxymethylcellulose and a suitable preservative.

Enteral compositions containing the compounds of this in en io y e d p nsed in do un t forms or a single daily therapeutic dose or in smaller units for multiple doses or in larger units for division into single doses. lParenteral compositions can also be dispensed with single units or in larger quantities from which each single dose is to be Withdrawn at the time of use.

Presently-preferred and practical embodiments of the present invention are illustratively shown in the following examples.

EXAMPLE 6 To a mixture of L-3-hydroxy-6-oxomorphinan (derived from thebaine) (0.235 g.), sodium bicarbonate (0.085 g.) and dimethylformamide (5 ml.), there is added a solution of cyclopropylmethyl chloride (0.091 g.) in dimethylformamide (5 ml.) with stirring. The resultant mixture is heated at a bath temperature of to C. on an oil bath. Twenty hours and 48 hours later, sodium bicarbonate (0.015 g.) and cyclopropylmethyl chloride (0.016 g.) are added respectively and heating is continued for 64 hours as a whole. After cooling, the reaction mixture is mixed with water (20 ml.) and shaken with chloroform. The chloroform layer is dried over anhydrous potassium carbonate to give a crude product (0.333 g.). The product is dissolved in 1 N sodium hydroxide aqueous solution (10 ml.), washed with benzene (20 ml.), made alkaline with ammonium chloride and shaken with chloroform. The chloroform layer is dried over anhydrous potassium carbonate and the chloroform is evaporated. The resulting crude product (0.269 g.) is recrystallized from acetone to give L-3-hydroxy-6-oxo-N-cyclopropylmethylmorphinan monohydrate (0.208 g.) as crystals melting at 127 to 128 C. The salicylate of this substance melts at 226 to 227 C. (decomp.).

EXAMPLE 2 A mixture of L 3 methoxy-6-oxo-14-hydroxy-morphinan (derived from thebaine) (1.1 g.) and 48% hydrobromic acid (11 ml.) is heated at to C. on an oil bath for 15 minutes and the excessive hydrobromic acid is evaporated. To the obtained L-3,14-dihydroxy-6- oxomorphinan hydrobromidc, there are added dimethylformamide (70 ml.) and sodium bicarbonate (0.380 g.) to neutralize the mixture. A solution of sodium bicarbonate (0.354 g.) and cyclopropylmethyl chloride (0.410 g.) in dimethylformamide (10 ml.) is added thereto and the resultant mixture is heated at a bath temperature of 110 to 115 C. on an oil bath. Twenty-two hours later, sodium bicarbonate (0.129 g.) and cyclopropylmethyl chloride (0.139 g.) are added thereto and heating is continued for 68 hours as a Whole. After cooling, the reaction mixture is combined with water (:100 ml.) and shaken with chloroform. The chloroform layer is dried over anhydrous potassium carbonate and the chloroform is evaporated. The residue (1.403 g.) is chromatographed on alumina (14 g.) eluting with chlorofrom to give L-3,l4- dihydroxy-6-oxo-N-cyclopropylmethylmorphinan monohydrate (0.828 g.). The substance is recrystallized from ethanol to give crystals melting at 181 to 182 C.

What is claimed is:

1. A member selected from the group consisting of a L-3-hydroxy-6-oxomorphinan compound represented by the formula:

wherein R represents a hydrogen atom or a hydroxyl group, R represents cyclopropylmethyl and F represents the presence or absence of a double bond and its medically acceptable acid addition salts.

2. A compound according to claim 1, said compound beinp L-3-hydroxy-6-oxo-N-cyclopropylrnethylmorphinan.

3. A compound according to claim 1, said compound being L 3, 14 dihydroxy 6 oxo-N-cyclopropylmethylmorphinan.

References Cited UNITED STATES PATENTS 3,393,197 7/1968 Pachter 260285 5 FOREIGN PATENTS 975,602 11/ 1964 Great Britain 260-285 4,017,021 8/1965 Japan 260-285 446,370 3/1968 Switzerland 260-285 10 DONALD G. DAUS, Primary Examiner 

